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Synthesis, pharmacokinetics and anticonvulsant activity of 7-chlorokynurenic acid prodrugs

Bonina, Francesco and Arenare, Loredana and Ippolito, Rosa and Boatto, Gianpiero and Battagla, Giuseppe and Bruno, Valeria and De Caprariis, Paolo (2000) Synthesis, pharmacokinetics and anticonvulsant activity of 7-chlorokynurenic acid prodrugs. International Journal of Pharmaceutics, Vol. 202 (1-2), p. 79-88. ISSN 0378-5173. Article.

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DOI: 10.1016/S0378-5173(00)00421-X

Abstract

7-Chlorokynurenic acid 1 is a potent glycine-N-methyl-D -aspartate (NMDA) receptor antagonist, but it shows weak activity after systemic administration. In order to overcome the Blood–brain barrier (BBB), we synthetized three new esters 2–4 of 1 obtained by chemical conjugation with essential nutrients such as glucose and galactose, that are actively transported across the BBB. These compounds were assayed to evaluate their in vitro chemical and enzymatic hydrolysis. In addition the prodrugs 2–4 were tested for their ability to protect mice against NMDA-induced seizures after systemic administration. All the prodrugs 2–4 appeared moderately stable in pH 7.4 buffered solution and were susceptible to in vitro enzymatic hydrolysis. Intraperitoneal administration of either esters 2 or 4 was highly protective against seizures induced by NMDA in mice, with the latter prodrug showing the highest anticonvulsive activity. In addition, ester 4 undergoes a time-dependent extracellular hydrolysis into 1 when applied to mixed cultures of mouse cortical cells, a model that reproduces in vitro the cellular milieu encountered by the prodrugs once they penetrate the brain parenchyma.

Item Type:Article
ID Code:5266
Status:Published
Refereed:Yes
Uncontrolled Keywords:Prodrug, 7-chlorokynurenic acid, blood–brain barrier, NMDA-receptor, anticonvulsant
Subjects:Area 03 - Scienze chimiche > CHIM/08 Chimica farmaceutica
Divisions:001 Università di Sassari > 01 Dipartimenti > Farmaco, chimico, tossicologico
Publisher:Elsevier Science
ISSN:0378-5173
Deposited On:20 Dec 2010 13:50

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